DESCRIPTION (Applicatnt's Abstract) The addictive properties of drugs of abuse such as psychostimulants depend on their ability to augment dopamine neurotransmission in the basal ganglia. The major target for dopaminergic neurons in the basal ganglia are the medium-sized spiny neurons. Our laboratory has accumulated considerable experience in the study of the intracellular signal transduction pathways regulated by dopamine in medium spiny neurons. This Program Project Grant proposes to elucidate the role of signal transduction pathways in the actions of drugs of abuse, particularly psychostimulants. A group of experts in various disciplines of biomedical research will carry out these studies using distinct but complementary approaches. Project I, entitled "Drugs of abuse: Role of cdk5 in actions of psychostimulants" will characterize of the role of cdkS and phosphorylation ofDARPP-32 in the actions of cocaine. These studies will utilize gene knockout mice to identify the contributions of selected elements of the cdk5/DARPP-32 signaling cascade. Project II, entitled, "Drugs of abuse: casein kinases 1 and 2, and the DARPP-32/protein phosphatase-l signaling cascade," will characterize the role of casein kinases and DARPP-32 in the actions of drugs of abuse, including psychostimulants, opiates, cannabinoids and caffeine. These studies will utilize gene knockout mice to identify the contributions of selected elements of the casein kinase l/casein kinase 21 DARPP-32 signaling cascade. Project III, entitled "Role of DARPP-16 and DARPP-21 in mediating the actions of drugs of abuse," will study the dopamine targets, DARPP-16 and DARPP-21 in the actions psychostimulants. These studies will utilize gene knockout mice, and will also examine the phosphorylation of DARPP-16 and DARPP-2l. Project IV, entitled "Novel molecular targets for drugs of abuse," will characterize the role of the protein phosphatase-l targeting proteins, spinophilin and neurabin, in the actions of psychostimulants. These studies will utilize gene knockout mice to identify the contributions of the spinophilin/protein phosphatase-l and neurabin/protein phosphatase-l signaling cascades. Finally, these studies will be supported by a Scientific Core that will provide maintenance of all colonies of knockout mice, and will produce key materials and perform routine, yet critical, tasks that will be required to accomplish the studies described in the other Projects.